Piperazine compounds

ABSTRACT

A compound selected from those of formula (I): 
                         
wherein:
         R 1 , R 2 , R 3  and R 4 , which may be the same or different, each represent an atom or group selected from hydrogen, halogen, alkyl, alkoxy, phenyl and cyano,   X represents a bond, an oxygen atom or a group selected from —(CH 2 ) m —, —OCH 2 — and —NR 5 —, wherein m represents 1 or 2, and R 5  is as defined in the description,   Y represents an oxygen atom or a group selected from NR 7  and CHR 8 , wherein R 7  and R 8  are as defined in the description,   Z represents a nitrogen atom or a CH group,   n represents 1 or 2,   Ak represents an alkylene chain,   Ar represents an aryl or heteroaryl group,
 
its optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
       
     Medical products containing the same which are useful in the treatment of conditions requiring a serotonin reuptake inhibitor and/or NK 1  antagonist.

The present invention relates to piperazine compounds, to a process fortheir preparation and to pharmaceutical compositions containing them,and also to their use as serotonin reuptake inhibitors.

By virtue thereof, they are useful in the treatment of depressive states(Goodnick and Goldstein, J Psychopharmacol 1998, 12 (Suppl B):S55-S87;Cheer and Goa, Drugs 2001, 61:81-110; MacQueen et al., CNS Drug Rev2001, 7:1-24; Wagstaff et al., Drugs 2002, 62:655-703), anxiety statessuch as generalized anxiety, panic attacks and phobias (Feighner, J ClinPsychiatry 1999, 60 (Suppl 22):18-22; Bakker et al., Int clinPsychopharmacol 2000, 15 (Suppl 2):S25-S30; Davidson, Int ClinPsychopharmacol 2000, 15 (suppl 1):S13-S17; Schneier, J Clin Psychiatry2001, 62 (Suppl 1):43-48), the harmful effect of stress whetherpsychological (Marona-Lewicka and Nichols, Stress 1997, 2:91-100; Mar etal., Pharmacol Biochem Behav 2002, 73:703-712; Will et al., MolPsychiatry 2003, 8:925-932; Ballenger, J Clin Psychiatry 2004,65:1696-1707) or neurotoxic (Malberg and Duman, Neuropsychopharmacology2003, 28:1562-1571; Santarelli et al., Science 2003, 301:805-809; Czehet al., Neuropsychopharmacology 2005, 30:67-79; Malberg and Schechter,Curr Pharm Des 2005, 11:145-155), impulsive states such as “ODC” orobsessive-compulsive behaviour disorders (Njung'e and Handley, Br JPharmacol 1991, 104:105-112; Ichimaru et al., Jpn J Pharmacol 1995,68:65-70; Pigott and Seay, J Clin Psychiatry 1999, 60:101-106;Vythilingum et al., Int Clin Psychopharmacol 2000, 15 (Suppl 2)S7-S13),aggressive states (Knutson et al., Am J Psychiatry 1998, 155:373-379;Lanctot et al., Neuropsychopharmacology 2002, 27:646-654; New et al.,Psychopharmacology 2004, 176:451-458), obesity and appetite disorderssuch as bulimia (Proietto et al., Expert Opin Investig Drugs 2000,9:1317-1326; Ljung et al., J Intern Med 2001, 250:219-224; Appolinarioet al., CNS Drugs 2004, 18:629-651; Appolinario and McElroy, Curr DrugTargets 2004, 5:301-307), pain states (Aragona et al., Eur J Pain 2005,9:33-38; Millan et al., Neuropharmacology 2002, 42:677-684; Duman etal., J Pharmacol Sci 2004, 94:161-165; Otsuka et al., J Anesth 2004,15:154-158); and, in relation to those entities, disorders of behaviourand of neuronal degeneration associated with dementia and otherdisorders of aging (Lyketos et al., Am J Psychiatry 2000, 157:1686-1689;Lanctot et al., J Neuropsyhiatry Clin Neurosci 2001, 13:5-21; Lanctot etal., Neuropsychopharmacology 2002, 27:646-654; Pollock et al., Am JPsychiatry 2002, 159:460-465).

Furthermore, most of the compounds of the present invention are alsoactive as neurokinin NK¹ antagonists.

By virtue thereof, they are also useful in the treatment of depressivestates (Rupniak et al., Behav Pharmacol 2001, 12:497-508; Rupniak etal., Neuropharmacology 2003, 44:516-523; Kramer et al.,Neuropsychopharmacology 2004, 29:385-392; Dableh et al., Eur J Pharmacol2005, 507:99-105), anxiety states such as generalised anxiety, panicattacks and phobias (Rupniak et al, Behav Pharmacol 2001, 12:497-508;Santarelli et al., Proc Natl Acad Sci USA 2001, 98:1912-1927; Varty etal., Neuropsychopharmacology 2002, 27:371-379; Rupniak and Kramer,Neuropsychopharmacology 2002, 13:169-177), the harmful effect of stresswhether psychological (Ballard et al., Eur J Pharmacol 2001,412:255-264; Rupniak and Kramer, Neuropsychopharmacology 2002,13:169-177; Spooren et al., Eur J Pharmacol 2002, 435:161-170; Steinberget al., J Pharmacol Exp Ther 2002, 303:1180-1188) or neurotoxic (Van derHart et al., Mol Psychiatry 2002, 7:933-941; Morcuende et al., Eur JNeurosci 2003, 18:1828-1836; Guest et al., Brain Res 2004, 1002:1-10;Czeh et al., Neuropsychopharmacology 2005, 30:67-79), impulsive statessuch as obsessive-compulsive behaviour disorders (Culman et al., Br JPharmacol 1995, 114:1310-1316; Tschöpe et al., Br J Pharmacol 1992,107:750-755; Rupniak et al., Behav Pharmacol 2001, 12:497-508; Millan etal., Neuropharmacology 2002, 42:677-684), aggressive states (Siegel andSchubert, Rev Neurosci 1995, 6:47-61; De Felipe et al., Nature 1998,392:394-397; Rupniak et al., Behav Pharmacol 2001, 12:497-508), but alsodrug abuse (Murtra et al., Nature 2000, 405:180-183; Ripley et al.,Neuropharmacology 2002, 43:1258-1268; Gadd et al., J Neurosci 2003,23:8271-8280), psychotic states (Zachrisson et al., EurNeuropsychopharmacol 2000, 10:355-363) and extrapyramidal motor effectscaused by antipsychotics (Anderson et al., J Pharmacol Exp Ther 1995,274:928-936, Steinberg et al., J Pharmacol Exp Ther 2002,303:1180-1188), sexual dysfunctions (Priest et al., Brain Res Mol BrainRes 1995, 28:61-71; Daniels et al., Neurosci Lett 2003, 338:111-114;Kramer et al., Science 1998, 281:1640-1644; Kramer et al.,Neuropsychopharmacology 2004, 29:385-392), disturbances ofchronobiological rhythms such as circadian rhythms (Shibata et al.,Brain Res 1992, 597:257-263; Challet et al., Brain Res 1998, 800:32-39;Challet et al., Neuropharmacology 2001, 40:408-415; Gannon et al.,Neuropharmacology, in press), pain (Seguin et al., Pain 1995,61:325-343; De Felipe et al., Nature 1998, 392:394-397; Sanger, Br JPharmacol 2004, 141:1303-1312) and/or inflammation (Seabrook et al., EurJ Pharmacol 1996, 317:129-135; Holzer, Digestion 1998, 59:269-283; Joosand Pauwels, Curr Opin Pharmacol 2001, 1:235-241; Sanger, Br J Pharmacol2004, 141:1303-1312), nausea and other gastrointestinal disorders(McAllister and Pratt Eur J Pharmacol 1998, 353:141-148; Gardner et al.,Regulatory Peptides 1996, 65:45-53; Patel and Lindley, Expert Opin.Pharmacother 2003, 4:2279-2296; Sanger, Br J Pharmacol 2004,141:1303-1312); and, in relation to those entities, disorders ofbehaviour and of neuronal degeneration associated with dementia andother disorders of aging (Raffa, Neurosci Biobehav Rev 1998,22:789-813).

The compounds that are active both on NK₁ receptors and on serotonin(5-HT) reuptake sites should have complementary and synergisticmechanisms for controlling impulsive, aggressive, painful and, aboveall, depressive states. It has moreover been shown that blocking NK₁receptors potentiates the influence of 5-HT reuptake inhibitors onserotoninergic transmission: because of that fact, such compounds shouldbring about more rapid and more robust antidepressant effects (Guiard etal., J Neurochem 2004, 89:54-63; Froger et al., J Neurosci 2001,21:8188-8197). The rapid anxiolytic effects of NK₁ antagonists should,moreover, be complementary to the anxiolytic effects of 5-HT reuptakeinhibitors, which are expressed after long-term treatment. With regardto the anxiogenic effects brought about by 5-HT at the start oftreatment (Bagdy et al., Int J Neuropsychopharmacol 2001, 4:399-408),these should be prevented by the NK₁ antagonist properties (Ballard etal., Eur J Pharmacol 2001, 412:255-264; Rupniak et al.,Neuropharmacology 2003, 44:516-523). As far as the other undesirableeffects associated with 5-HT reuptake blocking are concerned, such asemetic effects (Goldstein and Goodnick, J Psychopharmacol 1998, 12(Suppl B):S55-S87; Edwards and Anderson, Drugs 1999, 57:507-533; Waughand Goa, CNS Drugs 2003, 17:343-362) and the causation of sexualdysfunctions (Goldstein and Goodnick, J Psychopharmacol 1998, 12 (SupplB):S55-S87; Montgomery et al., J Affect disord 2002, 69:119-140;Hirschfeld, J Clin Psychiatry 2003, 64 (Suppl 18):20-24), NK₁antagonists should also be capable of counteracting those effects.

Consequently, the compounds that are both NK₁ antagonists and serotoninreuptake inhibitors should have therapeutic advantages over compoundsthat interact with only one or other of those two targets.

More specifically, the present invention relates to compounds of formula(I):

wherein

-   -   R₁, R₂, R₃ and R₄, which may be the same or different, each        represent an atom or group selected from H, halogen, linear or        branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, phenyl and        cyano,    -   X represents a bond, an oxygen atom or a group selected from        —(CH₂)_(m)—, —OCH₂— and —NR₅—,        -   m represents 1 or 2,        -   R₅ represents a hydrogen atom or a group selected from            linear or branched C₁-C₆alkyl, COR₆ and CO₂R₆,        -   R₆ represents a linear or branched C₁-C₆alkyl group,    -   Y represents an oxygen atom or a group selected from NR₇ and        CHR₈,        -   R₇ represents a hydrogen atom or a group selected from COR₉            and linear or branched C₁-C₆alkyl, the alkyl group being            optionally substituted by a            5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl or            2,3-dihydro-1,4-benzodioxin-2-yl group,        -   R₉ represents a group selected from linear or branched            C₁-C₆alkyl, aryl and heteroaryl,        -   R₈ represents a hydrogen atom or an amino group optionally            substituted by one or two linear or branched C₁-C₆alkyl            groups,    -   Z represents a nitrogen atom or a CH group,    -   n represents 1 or 2,    -   Ak represents a linear or branched C₁-C₆alkylene chain,    -   Ar represents an aryl or heteroaryl group,        to their optical isomers, and also to addition salts thereof        with a pharmaceutically acceptable acid.

Optical isomers are understood to mean enantiomers and diastereoisomers.

Among the pharmaceutically acceptable acids there may be mentioned,without implying any limitation, hydrochloric acid, hydrobromic acid,sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,oxalic acid, methanesulphonic acid, benzenesulphonic acid, camphoricacid, dibenzoyltartaric acid.

An aryl group is understood to mean phenyl, biphenylyl or naphthyl, eachof those groups optionally being substituted by one or more identical ordifferent groups selected from halogen, linear or branched C₁-C₆alkyl,linear or branched C₁-C₆alkoxy, hydroxy, cyano, linear or branchedC₁-C₆trihaloalkyl and linear or branched C₁-C₆trihaloalkoxy.

A heteroaryl group is understood to mean an aromatic mono- or bi-cyclic5- to 12-membered group containing one, two or three hetero atomsselected from oxygen, nitrogen and sulphur, it being understood that theheteroaryl group may optionally be substituted by one or more identicalor different groups selected from halogen, linear or branchedC₁-C₆alkyl, linear or branched C₁-C₆alkoxy, hydroxy, cyano and linear orbranched C₁-C₆trihaloalkyl.

X preferably represents a bond, an oxygen atom or a group selected from—OCH₂— and —(CH₂)_(m)— wherein m represents 1 or 2.

Y preferably represents NH.

Z preferably represents a nitrogen atom.

n preferably represent 1.

Ar preferably represents an aryl group.

Preferred compounds according to the invention are:

-   -   trans-1-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   trans-1-{3-[(3,5-dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   trans-1-{6-[(3,5-dibromobenzyl)oxy]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}-piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   trans-1-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   trans-1-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}-1,4-diazepane,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   1-{(1S,2R)-2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   1-[(1S,2R)-2-[(3,5-difluorobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl]piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   1-[(1S,2R)-2-[(3,5-dimethylbenzyl)oxy]-2,3-dihydro-1H-inden-1-yl]piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   trans-1-{3-[(3,5-dichlorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   trans-1-{3-[3-fluoro-5-(trifluoromethyl)benzyloxy]-3,4-dihydro-2H-chromen-4-yl}-piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid,    -   and        trans-1-{3-(3-chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazine,        its enantiomers, and also addition salts thereof with a        pharmaceutically acceptable acid.

The invention relates also to a process for the preparation of compoundsof formula (I), starting from the compound of formula (Va), of relativeconfiguration trans:

wherein R₁, R₂, R₃, R₄, X, n and Z are as defined hereinbefore, and Y′represents an oxygen atom or a group selected from NP₁ and CHR′₈,wherein R′₈ represents a hydrogen atom or a group NHP₁, and P₁represents a protecting group for the amine function,

-   -   which compound of formula (Va) is reacted, when it is desired to        obtain compounds of formula (I) of relative configuration trans,        with a compound of formula (VI):        G-Ak-Ar  (VI),        wherein Ak and Ar are as defined for formula (I), and G        represents a leaving group such as, for example, a halogen atom        or a p-toluenesulphonate, trifluoromethanesulphonate or        methanesulphonate group,

-   to yield the compound of formula (VIIa), of relative configuration    trans:

wherein R₁, R₂, R₃, R₄, X, n, Y′, Z, Ak and Ar are as definedhereinbefore,

-   which is deprotected when Y′ contains a protecting group P₁ as    defined hereinbefore and is then alkylated, when it is desired to    obtain compounds wherein Y represents a group NR₇ wherein R₇ is    other than a hydrogen atom,-   to yield compounds of formula (Ia), a particular case of the    compounds of formula (I), which are of relative configuration trans:

wherein R₁, R₂, R₃, R₄, X, n, Y, Z, Ak and Ar are as defined for formula(I),

-   -   or which compound of formula (Va) is oxidised, when it is        desired to obtain compounds of formula (I) of relative        configuration cis,

-   to yield the racemic compound of formula (VIII):

wherein R₁, R₂, R₃, R₄, X, Z, n and Y′ are as defined hereinbefore,

-   which is reduced to the corresponding alcohol, the diastereoisomers    of which are separated, and the isomer of formula (Vb), of relative    configuration cis, is isolated:

wherein R₁, R₂, R₃, R₄, X, Y′, Z and n are as defined hereinbefore,

-   which is reacted with a compound of formula (VI) as defined    hereinbefore to yield the compound of formula (VIIb), of relative    configuration cis:

wherein R₁, R₂, R₃, R₄, X, n, Y′, Z, Ak and Ar are as definedhereinbefore,

-   which is deprotected when Y′ contains a protecting group P₁ as    defined hereinbefore and is then alkylated, when it is desired to    obtain compounds wherein Y represents a group NR₇ wherein R₇ is    other than a hydrogen atom,-   to yield compounds of formula (Ib), a particular case of the    compounds of formula (I), which are of relative configuration cis:

wherein R₁, R₂, R₃, R₄, X, Y, Z, n, Ak and Ar are as defined for formula(I),

-   which compounds of formulae (Ia) and (Ib) may be purified according    to a conventional purification technique, are separated, when    desired, into their optical isomers and are converted, when desired,    into their addition salts with a pharmaceutically acceptable acid.

The compounds of formula (Ic), a particular case of compounds of formula(I) wherein Ak represents a group —CH(CH₃)—:

wherein R₁, R₂, R₃, R₄, X, n, Y, Z and Ar are as defined for formula(I),

-   may also be prepared by condensation of the alcohol of formula (Va)    or (Vb) with an acid of formula (IX):    HO₂C—Ar  (IX),    wherein Ar is as defined for formula (I),-   to yield the ester of formula (X)

wherein R₁, R₂, R₃, R₄, X, n, Y′, Z and Ar are as defined hereinbefore,

-   which is reacted with bis(cyclopentadienyl)dimethyltitanium, to    yield the compound of formula (XI):

wherein R₁, R₂, R₃, R₄, X, n, Y′, Z and Ar are as defined hereinbefore,

-   which is hydrogenated to yield the compound of formula (XII):

wherein R₁, R₂, R₃, R₄, X, n, Y′, Z and Ar are as defined hereinbefore,

-   which is separated into its isomers and is then deprotected when Y′    contains a protecting group P₁ as defined hereinbefore and    alkylated, when it is desired to obtain compounds wherein Y    represents a group NR₇ wherein R₇ is other than a hydrogen atom, to    yield compounds of formula (Ic).

The compounds of formula (Va₁), a particular case of compounds offormula (Va) wherein Z represents a nitrogen atom, may be preparedstarting from the compound of formula (II):

wherein R₁, R₂, R₃, R₄ and X are as defined for formula (I),

-   which is oxidised into the compound of formula (III):

wherein R₁, R₂, R₃, R₄ and X are as defined hereinbefore,

-   which is reacted with the compound of formula (IV):

wherein n is as defined for formula (I) and Y′ is as definedhereinbefore,

-   to yield the compound of formula (Va₁):

wherein R₁, R₂, R₃, R₄, X, Y′ and n are as defined hereinbefore.

The compounds of formula (Va₂), a particular case of the compounds offormula (Va) wherein Z represents a CH group, n represents 1 and Y′represents a NP₁ group, may be prepared starting from the compound offormula (XIII):

wherein R₁, R₂, R₃, R₄ and X are as defined hereinbefore,

-   which is reacted with 4-pyridyllithium to yield the compound of    formula (XIV):

wherein R₁, R₂, R₃, R₄ and X are as defined hereinbefore,

-   which is dehydrated to yield the compound of formula (XV):

wherein R₁, R₂, R₃, R₄ and X are as defined hereinbefore,

-   which is reacted with Oxone to yield the compound of formula (XVI):

wherein R₁, R₂, R₃, R₄ and X are as defined hereinbefore,

-   which is reacted with a reducing agent to yield the compound of    formula (XVII):

wherein R₁, R₂, R₃, R₄ and X are as defined hereinbefore,

-   which is subjected to a catalytic hydrogenation reaction to yield    the compound of formula (XVIII):

wherein R₁, R₂, R₃, R₄ and X are as defined hereinbefore,

-   the cis and trans isomers of which are separated, the amine function    of the trans isomer of which is protected to yield the compound of    formula (Va₂), of relative configuration trans:

wherein R₁, R₂, R₃, R₄ and X are as defined hereinbefore.

The compounds of the present invention are serotonin reuptakeinhibitors, and most of them are also NK₁ antagonists. They are usefulas medicaments in the treatment of depressive states, anxiety states,impulsive disorders, aggressive behaviours, drug abuse, obesity andappetite disorders, pain and inflammation, dementias, psychotic states,disturbances of chronobiological rhythms, nausea and gastrointestinaldisorders.

The present invention relates also to pharmaceutical compositionscomprising, as active ingredient, a compound of formula (I), or anaddition salt thereof with a pharmaceutically acceptable acid, incombination with one or more pharmaceutically acceptable, inert,non-toxic excipients or carriers.

Among the pharmaceutical compositions according to the invention theremay be mentioned more especially those that are suitable for oral,parenteral (intravenous, intramuscular or subcutaneous), per- ortrans-cutaneous, nasal, rectal, perlingual, ocular or respiratoryadministration, and especially tablets or dragées, sublingual tablets,gelatin capsules, capsules, suppositories, creams, ointments, dermalgels, injectable or drinkable preparations, aerosols, eye drops and nosedrops.

The useful dosage varies according to the age and weight of the patient,the administration route, the nature and severity of the disorder, andthe administration of any associated treatments and ranges from 0.5 to500 mg per day in one or more administrations.

The Examples that follow illustrate the invention. The startingmaterials used are known products or are prepared according to knownprocedures. The various Preparations yield synthesis intermediates thatare of use in preparation of the compounds of the invention.

The structures of the compounds described in the Examples weredetermined according to customary spectrophotometric techniques(infra-red, nuclear magnetic resonance, mass spectrometry).

The melting points were determined either on a Kofler bench (BK) or on ahot-plate under a microscope (MK).

Preparation A: 6-Bromo-1,2-dihydronaphthalene Step A:7-Bromo-1,2,3,4-tetrahydronaphth-1-ol

To 9.5 g of 7-bromo-3,4-dihydronaphthalen-1(2H)-one (42 mmol), preparedaccording to the method described in Synth. Comm. 1994, 2777, dissolvedin 100 ml of ethanol, there are added, at 0° C. and in two portions,0.8g of sodium borohydride (21 mmol). The reaction mixture is then allowedto come back up to ambient temperature over 30 minutes, and then theethanol is evaporated off. The residue is taken up in 100 ml of tolueneand 100 ml of water. After separation, the aqueous phase is extractedwith 50 ml of toluene. The toluene phases are combined, washed with asaturated aqueous solution of sodium chloride and are then evaporated toyield 7-bromo-1,2,3,4-tetrahydronaphth-1-ol in the form of an oil.

Step B: 6-Bromo-1,2-dihydronaphthalene

A solution of 8.6 g of the compound obtained in the Step above (37.9mmol) in 200 ml of toluene is heated to 100° C. At that temperaturethere is added dropwise, over one hour, a solution of 0.3 g ofpara-toluenesulphonic acid (1.2 mmol) dissolved in 400 ml of toluene.The reaction mixture is subsequently cooled to 25° C. and thenhydrolysed using 100 ml of water. The organic phase is extracted andthen dried, filtered and evaporated to yield6-bromo-1,2-dihydronaphthalene in the form of an oil.

Preparation B: 7-Bromo-2,3-dihydro-1-benzoxepin Step A:4-[5-Bromo-2-(but-3-en-1-yloxy)phenyl]-4-hydroxybutan-2-one

To 300 ml of acetone there are added 10 g of5-bromo-2-hydroxybenzaldehyde (49.7 mmol), 13.7 g of potassium carbonate(99.5 mmol) and 10.1 ml of 4-bromobut-1-ene (99.5 mmol); the reactionmixture is then heated at reflux for 36 hours before being cooled,filtered and evaporated to dryness to yield4-[5-bromo-2-(but-3-en-1-yloxy)phenyl]-4-hydroxybutan-2-one in the formof an oil.

Step B: 4-Bromo-1-(but-3-en-1-yloxy)-2-vinylbenzene

To 90 ml of anhydrous tetrahydrofuran there are added 1.6 g of 60%sodium hydride in oil (39.8 mmol) and then, at 0° C. and all at once,10.67 g of methyl(triphenyl)phosphonium bromide (29.9 mmol).

The mixture is allowed to come back up to ambient temperature and isstirred for is 30 minutes at 25° C. A solution of 8 g of the compoundobtained in the Step above (24.9 mmol) in 30 ml of anhydroustetrahydrofuran is then added dropwise to the reaction mixture, atambient temperature. An exothermic reaction from 25° C. to 35° C. isobserved over 45 minutes. Stirring is carried out for a further 2 hoursat ambient temperature; the reaction mixture is then filtered and thefiltrate is poured into a mixture of 100 ml of ethyl acetate, 200 ml ofa saturated aqueous solution of sodium chloride and 50 g of ice. Afterextraction with ethyl acetate, the combined organic phases are washedwith water, dried, filtered and evaporated to dryness. The residueobtained is purified by filtration over 100 g of silica (eluant: toluene100%) to yield 4-bromo-1-(but-3-en-1-yloxy)-2-vinylbenzene in the formof an oil.

Step C: 7-Bromo-2,3-dihydro-1-benzoxepin

5 g of the compound obtained in the Step above (19.8 mmol) are dissolvedin 500 ml of toluene, and the solution is then degassed for 30 minutesusing nitrogen. 335 mg (0.39 mmol) of[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium],or Grubb's II catalyst, are added. The reaction mixture is then heatedat 50° C. for 30 minutes; the toluene is then evaporated off and theresidue obtained is purified on a column of 70 g of silica (eluant:cyclohexane/toluene: 95/5) to yield 7-bromo-2,3-dihydro-1-benzoxepin.

EXAMPLE 1trans-1-{2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-piperazinedihydrochloride Step A: tert-Butyltrans-4-(2-hydroxy-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate

11.6 g of tert-butyl piperazine-1-carboxylate (62 mmol) and 8.2 g ofindene oxide (62 mmol) are dissolved in 30 ml of acetonitrile. Thereaction mixture is then heated at 60° C. overnight and evaporated todryness. The residue obtained is purified by flash chromatography on 1kg of silica (eluant: dichloromethane/ethanol 95/5) to yield tert-butyltrans-4-(2-hydroxy-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate inthe form of a white meringue.

Step B: tert-Butyltrans-4-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-piperazine-1-carboxylate

To 3 g of the compound obtained in the Step above (9.42 mmol) in 30 mlof anhydrous dimethylformamide there are added 452 mg of sodium hydrideas a 60% suspension in oil (11.3 mmol, 1.2 equivalents). After stirringfor 30 minutes at ambient temperature there are added 3.1 g of3,5-dibromobenzyl bromide (9.42 mmol). A slight exothermic reaction isobserved. The reaction mixture is then stirred overnight at ambienttemperature, and subsequently the dimethylformamide is evaporated off.The residue obtained is taken up in dichloromethane. After washing withwater, drying, filtration and evaporation, there are obtained 6 g of aresidue which is purified by flash chromatography on 500 g of silica(eluant: dichloromethane/ethyl acetate 90/10) to yield tert-butyltrans-4-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylatein the form of a meringue.

Step C:trans-1-{2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride

3.5 g of the compound obtained in the Step above (6.18 mmol) aredissolved in 250 ml of ethyl acetate and then gaseous hydrogen chlorideis bubbled through the solution. The temperature is allowed to increaseto 45° C., and stirring is then carried out for 2 hours at ambienttemperature. The reaction mixture is then concentrated to two-thirds andthen 50 ml of ether are added. The precipitate obtained is filtered offand then dried to yieldtrans-1-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride in the form of a beige solid.

Melting point (MK): 154-167° C.

EXAMPLE 2 (−) isomer oftrans-1-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride

After reconversion to the base, the racemic compound of Example 1 isseparated by preparative chiral HPLC chromatography (eluant:isopropanol/acetonitrile/diethylamine 100/900/1) on a Chiralpak ADphase. The first of the isomers thereby separated is converted into asalt using hydrochloric acid to yield the dihydrochloride of the (−)isomer oftrans-1-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine.

Melting point (MK): 117-125° C. Optical rotation: [α]_(D)=−27.86 (c=1%,MeOH, 20° C., 589 nm).

EXAMPLE 3 (+) isomer oftrans-1-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride

The second of the isomers separated in Example 2 is converted into asalt using hydrochloric acid to yield the dihydrochloride of the (+)isomer oftrans-1-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine.

Melting point (MK): 115-121° C. Optical rotation: [α]_(D)=+27.29 (c=1%,MeOH, 20° C., 589 nm)

EXAMPLE 4trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride Step A: trans-3-Bromochroman-4-ol

To 15 g of 2H-chromene (0.113 mol) dissolved in 330 ml of a mixture oftetrahydrofuran/water 50/50 there are added 22.1 g of N-bromosuccinimide(0.124 mol, 1.1 equivalents), and the mixture is then stirred for onehour at ambient temperature. The reaction mixture is then diluted withwater, and subsequently extracted twice with ethyl acetate. The combinedorganic phases are washed with water, dried, filtered and evaporated todryness to yield trans-3-bromochroman-4-ol in the form of a pale-yellowsolid.

Melting point (BK): 96-98° C.

Step B: 1a,7b-Dihydro-2H-oxireno[c]chromene

4.4 g of potassium hydroxide pellets (78.5 mmol) are added to 10 g ofthe compound obtained in the Step above (43.6 mmol), dissolved in 170 mlof tetrahydrofuran and 85 ml of water. After stirring for 2 hours at 25°C., the reaction mixture is diluted with water and extracted twice withether. The organic phases are combined and washed with water, dried,filtered and evaporated to dryness to yield1a,7b-dihydro-2H-oxireno[c]chromene in the form of a pale-yellow oil.

Step C: tert-Butyltrans-4-(3-hydroxy-3,4-dihydro-2H-chromen-4-yl)piperazine-1-carboxylate

4.9 g of the compound obtained in the Step above (33 mmol) are treatedwith 6.1 g of tert-butyl piperazine-1-carboxylate (33 mmol) according tothe method described in Step A of Example 1. The oil obtained ispurified by flash chromatography on 500 g of silica (eluant:dichloromethane/ethanol 95/5) to yield the expected product in the formof an oil.

Step D: tert-Butyltrans-4-{3-[(3,5-dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-piperazine-1-carboxylate

3 g of the compound obtained in the Step above (8.9 mmol) are treatedaccording to the method described in Step B of Example 1. The oilobtained is purified by flash chromatography on 300 g of silica to yieldthe expected product in the form of a white meringue.

Step E:trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-piperazinedihydrochloride

2.9 g of the compound obtained in the Step above (4.97 mmol) are treatedaccording to the method described in Step C of Example 1. The productobtained is crystallised from ether, filtered and dried to yield theexpected product in the form of white crystals.

Melting point (MK): 130-135° C.

EXAMPLE 5 (−) isomer oftrans-1-{3-[(3,5-dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

After reconversion to the base, the racemic compound of Example 4 isseparated by preparative chiral HPLC chromatography (eluant:ethanol/diethylamine 1000/1) on a Chiralpak AD phase. The first of theisomers thereby separated is converted into a salt using hydrochloricacid to yield the dihydrochloride of the (−) isomer oftrans-1-{3-[(3,5-dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazine.

Melting point (MK): 128-132° C. Optical rotation: [α]_(D)=−40.36 (c=1%,MeOH, 20° C., 589 nm).

EXAMPLE 6 (+) isomer oftrans-1-{3-[(3,5-dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The second of the isomers separated in Example 5 is converted into asalt using hydrochloric acid to yield the dihydrochloride of the (+)isomer oftrans-1-{3-[(3,5-dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazine.

Melting point (MK): 126-130° C. Optical rotation: [α]_(D)=+40.92 (c=1%,MeOH, 20° C., 589 nm).

EXAMPLE 7trans-1-{6-[(3,5-Dibromobenzyl)oxy]-6,7,8,9-tetrahydro-5H-benzo-[7]annulen-5-yl}piperazinedihydrochloride Step A: tert-Butyltrans-4-(6-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-piperazine-1-carboxylate

The expected product is obtained according to the procedure described inSteps A, B and C of Example 4, replacing the 2H-chromene by6,7-dihydro-5H-benzo[7]annulene.

Step B:trans-1-{6-[(3,5-Dibromobenzyl)oxy]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure described inSteps B and C of Example 1, starting from the compound obtained in theStep above.

Melting point (MK): 126-131° C.

EXAMPLE 8trans-1-{4-[(3,5-Dibromobenzyl)oxy]-2,3,4,5-tetrahydro-1-benzoxepin-5-yl}piperazinedihydrochloride Step A: 1a,2,3,8b-Tetrahydrooxireno[d][1]benzoxepin

To 0.5 g of 2,3-dihydro-1-benzoxepin (3.42 mmol), prepared according tothe method described in J. Org. Chem., 1969, 34 (1), 207, dissolved in30 ml of a mixture of ethyl acetate/water 50/50, there are added 1.44 gof sodium hydrogen carbonate (17.1 mmol) and then, over 1 hour, asolution of 2.1 g of Oxone® (3.42 mmol) in 15 ml of water. After the endof the addition, stirring is carried out for a further hour and then theorganic phase is separated off. The aqueous phase is again extractedwith 10 ml of ethyl acetate, and the combined organic phases are washedwith water, dried, filtered and evaporated to dryness to yield theexpected product in the form of an oil.

Step B: tert-Butyltrans-4-(4-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-5-yl)piperazine-1-carboxylate

The expected product is obtained according to the procedure described inStep A of Example 1, starting from the compound obtained in the Stepabove.

Step C:trans-1-{4-[(3,5-Dibromobenzyl)oxy]-2,3,4,5-tetrahydro-1-benzoxepin-5-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure described inSteps B and C of Example 1, starting from the compound obtained in theStep above.

Melting point (MK): 132-139° C.

EXAMPLE 9trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperidin-4-aminedihydrochloride Step A: tert-Butyltrans-[1-(3-hydroxy-3,4-dihydro-2H-chromen-4-yl)piperidin-4-yl]-carbamate

To 3 g of the compound obtained in Step B of Example 4, dissolved in 45ml of acetonitrile, there are added 4 g of tert-butylpiperidin-4-ylcarbamate (20.2 mmol). The mixture is then heated atreflux for 12 hours and subsequently evaporated to dryness. A yellow oilis obtained which is purified by flash chromatography on silica (eluant:dichloromethane/ethanol 95/5) to yield the expected product in the formof a pale-yellow meringue.

Step B: tert-Butyltrans-1-{3-[(3,5-dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-4-piperidylcarbamate

The expected product is obtained according to the procedure described inStep B of Example 1, starting from the compound obtained in the Stepabove.

Step C:trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperidin-4-aminedihydrochloride

The expected product is obtained according to the procedure described inStep C of Example 1, starting from the compound obtained in the Stepabove.

Melting point (MK): 160-165° C.

EXAMPLE 10trans-4-{2-[(3,5-Dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}morpholinehydrochloride Step A: 1a,2,3,7b-Tetrahydronaphtho[1,2-b]oxirene

36.5 g of 1,2-dihydronaphthalene (280.3 mmol) are treated with Oxone®according to the method described in Step A of Example 8 to yield theexpected product in the form of an oil.

Step B: trans-1-Morpholin-4-yl-1,2,3,4-tetrahydronaphth-2-ol

To 3.95 g of the compound obtained in the Step above (27.02 mmol),dissolved in 65 ml of acetonitrile, there are added 2.35 ml ofmorpholine (27.02 mmol), and then 185 mg of ZnCl₂ (1.35 mmol). Afterheating at reflux for 12 hours, the mixture is evaporated to dryness andthe residue obtained is purified by flash chromatography on silica(dichloromethane/ethanol 95/5) to yield the expected product in the formof a light-brown solid.

Melting point (BK): 88-90° C.

Step C:trans-4-{2-[(3,5-Dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}morpholine

3 g of the compound obtained in the Step above (12.85 mmol) are treatedaccording to the method described in Step B of Example 1. An oil isobtained which is purified by flash chromatography on silica (eluant:dichloromethane) to yield the expected product in the form of an oil.

Step D:trans-4-{2-[(3,5-Dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}morpholinehydrochloride

To 1.9 g of the compound obtained in the Step above (3.95 mmol),dissolved in 40 ml of ethyl acetate, there are added 2.96 ml of a 2Methereal HCl solution (5.92 mmol). After filtration and drying of thecrystals, the expected product is obtained.

Melting point: (MK)=175-180° C.

EXAMPLE 11trans-1-{2-[(3,5-Dibromobenzyl)oxy]-5-methoxy-2,3-dihydro-1H-inden-1-yl}piperazineStep A: 4-Methoxy-6,6a-dihydro-1aH-indeno[1,2-b]oxirene

The expected product is obtained according to the procedure described inSteps A and B of Example 4, starting from 6-methoxy-1H-indene.

Step B: tert-Butyltrans-4-{2-[(3,5-dibromobenzyl)oxy]-5-methoxy-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate

The expected product is obtained according to the procedure described inSteps A and B of Example 1, starting from the compound obtained in theStep above.

Step C:trans-1-{2-[(3,5-Dibromobenzyl)oxy]-5-methoxy-2,3-dihydro-1H-inden-1-yl}-piperazine

1.3 g of the compound obtained in the Step above (2.17 mmol) are treatedaccording to the method described in Step C of Example 1. Afterevaporation to dryness, the product obtained is taken up in water, andthe aqueous phase is adjusted to pH 8 by adding sodium hydroxidesolution (1N) and extracted with ether. The organic phase is washed withwater, dried, filtered and evaporated to dryness. The residue obtainedis crystallised from isopropyl ether. The crystals are filtered off anddried to yield the expected product.

Melting point (MK): 101-104° C.

EXAMPLE 12trans-1-{2-[(3,5-Dibromobenzyl)oxy]-7-methoxy-1,2,3,4-tetrahydronaphth-1-yl}piperazinedihydrochloride Step A: 2-Bromo-7-methoxy-1,2,3,4-tetrahydronaphth-1-ol

20 g of 6-methoxy-1,2-dihydronaphthalene (126 mmol) are treatedaccording to the method described in Step A of Example 4 to yield theexpected product.

Step B: tert-Butyltrans-4-(2-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphth-1-yl)-piperazine-1-carboxylate

To 2 g of the compound obtained in the Step above (7.78 mmol), dissolvedin 30 ml of tetrahydrofuran, there are added 1.24 g of sodium hydride asa 60% suspension in oil (31.1 mmol) and stirring is carried out for 4hours at ambient temperature. The reaction mixture is filtered. Thefiltrate, which contains6-methoxy-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene in solution, is thenreacted with 1.5 g of tert-butyl piperazine-1-carboxylate (7.78 mmol)and 5 ml of dimethylformamide. The tetrahydrofuran is distilled off fromthe reaction mixture, which is then heated at 110° C. for 24 hours. Themixture is cooled, poured into water and extracted with dichloromethane.The organic phase is dried and then filtered and evaporated to dryness.The residue obtained is purified by flash chromatography on silica(eluant: dichloromethane/ethanol: 98/2) to yield the expected product.

Step C:trans-1-{2-[(3,5-Dibromobenzyl)oxy]-7-methoxy-1,2,3,4-tetrahydronaphth-1-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure described inSteps B and C of Example 1, starting from the compound obtained in theStep above.

Melting point (MK): 175-182° C.

EXAMPLE 13trans-1-{2-[(3,5-Dibromobenzyl)oxy]-6-methoxy-1,2,3,4-tetrahydronaphth-1-yl}piperazinedihydrochloride Step A: 2-Bromo-6-methoxy-1,2,3,4-tetrahydronaphth-1-ol

10.8 g of 7-methoxy-1,2-dihydronaphthalene (67.4 mmol) are treatedaccording to the method described in Step A of Example 4 to yield theexpected product.

Step B: tert-Butyltrans-4-(2-hydroxy-6-methoxy-1,2,3,4-tetrahydronaphth-1-yl)-piperazine-1-carboxylate

To 9.7 g of the compound obtained in the Step above (37.8 mmol),dissolved in 150 ml of tetrahydrofuran, there are added 3 g of sodiumhydride as a 60% suspension in oil (75.6 mmol, 2 equivalents), and thenthe reaction mixture is stirred for 24 hours at ambient temperature.After filtration, the filtrate, which contains5-methoxy-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene in solution, isreacted with 8.4 g of tert-butyl piperazine-1-carboxylate (45.3 mmol) in20 ml of dimethylformamide. The tetrahydrofuran is then distilled off,and the reaction mixture is subsequently heated at 110° C. for 1 hour.The reaction mixture is then cooled before being poured into water andextracted with dichloromethane. The organic phase is then dried,filtered and evaporated to dryness to yield a residue which is purifiedby flash chromatography on silica (eluant: dichloromethane/ethanol:98/2) to yield the expected product.

Step C:trans-1-{2-[(3,5-Dibromobenzyl)oxy]-6-methoxy-1,2,3,4-tetrahydronaphth-1-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure described inSteps B and C of Example 1, starting from the compound obtained in theStep above.

Melting point (MK): 137-150° C.

EXAMPLE 14trans-1-{2-[(3,5-Dibromobenzyl)oxy]-5-phenyl-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, starting from 6-phenyl-1H-indene.

Melting point (MK): 145-153° C.

EXAMPLE 15trans-1-{2-[(3,5-Dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}piperazinedihydrochloride Step A: trans-2-Bromo-1,2,3,4-tetrahydronaphth-1-ol

To 13.0 g (100 mmol) of dihydronaphthalene, dissolved in a mixture of100 ml of water and 400 ml of tetrahydrofuran, at ambient temperature,there are added, all at once, 19.6 g (110 mmol) of N-bromosuccinimideand stirring is carried out for 3 hours. There are then added 200 ml ofice-cold water and 200 ml of ether; stirring is carried out and thephases are separated. The aqueous phase is extracted with 200 ml ofether; the combined organic phases are then washed with 200 ml of asaturated aqueous solution of sodium chloride and dried and thenevaporated to yield the expected compound.

Step B: 1a,2,3,7b-Tetrahydronaphtho[1,2-b]oxirene

To 27.5 g of the compound obtained in the Step above, dissolved in 180ml of tetrahydrofuran, there is added dropwise, over 5 minutes, atambient temperature, a solution of 10 g (180 mmol) of potassiumhydroxide in 10 ml of water. After stirring for 5 days at ambienttemperature, 200 ml of water are added and extraction is carried outwith ethyl ether. The combined organic phases are washed and then dried.After evaporation, the product obtained is distilled in vacuo(approximately 0.1 mm Hg) in a Kugelrohr apparatus. The expected productdistils at around 80° C.

Step C: tert-Butyl4-[trans-2-hydroxy-1,2,3,4-tetrahydronaphth-1-yl]piperazine-1-carboxylate

At ambient temperature, 4.4 g (30 mmol) of the compound obtained in theStep above and 5.6 g (30 mmol) of N-tert-butyloxycarbonylpiperazine in60 ml of acetonitrile are mixed together and then heated at reflux for40 hours. After evaporation and flash chromatography on 500 g of silica(eluant: dichloromethane/ethanol 98/2), the expected product iscollected.

Step D: tert-Butyl4-{trans-2-[(3,5-dibromobenzyl)oxy-]-1,2,3,4-tetrahydronaphth-1-yl}piperazine-1-carboxylate

At ambient temperature, to 0.44 g (11 mmol) of sodium hydride as asuspension in 20 ml of tetrahydrofuran there are added, over a fewminutes, 3.3 g (10 mmol) of the compound obtained in the Step above,dissolved in 20 ml of tetrahydrofuran. The mixture is heated at 50° C.for 2 hours and there are then added, all at once, 3.3 g (10 mmol) of3,5-dibromobenzyl bromide, and then 3.7 g (10 mmol) oftetra-n-butylammonium iodide, and heating is carried out overnight at70° C. The mixture is then poured into 100 ml of water and extractionwith two quantities, each of 100 ml, of ethyl ether is carried out. Thecombined organic phases are washed and dried. After evaporation andflash chromatography on 300 g of silica (eluant: dichloromethane 100%,and then dichloromethane/ethyl acetate 90/10), the expected compound iscollected.

Step E:trans-1-{2-[(3,5-Dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}piperazinedihydrochloride

Gaseous hydrogen chloride is bubbled through 5.8 g (10 mmol) of theabove compound dissolved in 400 ml of ethyl acetate, at ambienttemperature, for a few minutes. Stirring is then carried out for 3 hoursat ambient temperature; the mixture is then concentrated by half (aprecipitate appears) and 100 ml of ether are added; stirring is thencarried out overnight at ambient temperature. After filtering off,rinsing and drying the precipitate, the expected compound is collectedin racemic form.

Melting point (M.K.): 110-125° C.

EXAMPLE 16 (−) isomer oftrans-1-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}piperazinedihydrochloride

After reconversion to the base, the racemic compound obtained in Example15 is separated by preparative chiral HPLC chromatography on a CHIRALPAKAD column (eluant: acetonitrile/isopropanol/diethylamine 900/100/1). Thefirst of the isomers thereby separated is converted into thehydrochloride salt using ethanolic HCl, and is then precipitated fromether. After filtering, rinsing and drying, the (−) enantiomer isobtained in an enantiomeric excess of more than 98%.

Melting point (M.K.): 113-126° C. Optical rotation: [α]=−14.5 (c=1%,MeOH, 20° C., λ=589 nm)

EXAMPLE 17 (+) isomer oftrans-1-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}piperazinedihydrochloride

The second of the isomers separated in Example 16 is converted into ahydrochloride to yield the expected product.

Melting point (M.K.): 118-126° C. Optical rotation: [α]=+14.4 (c=1%,MeOH, 20° C., λ=589 nm)

EXAMPLE 18trans-1-{2-[(3,5-Dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}-1,4-diazepanedihydrochloride Step A: tert-Butyltrans-4-[2-hydroxy-1,2,3,4-tetrahydronaphth-1-yl]-1,4-diazepane-1-carboxylate

At ambient temperature, 3.0 g (20.5 mmol) of the compound obtained inStep B of Example 15 and 4.1 g (20.5 mmol) ofN-tert-butyloxycarbonyl-homopiperazine in 41 ml of acetonitrile aremixed together and then heated at reflux for 48 hours. After evaporationand flash chromatography on 300 g of silica (eluant:dichloromethane/ethanol 98/2), the expected compound is collected.

Step B: tert-Butyltrans-4-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}-1,4-diazepane-1-carboxylate

At ambient temperature, to 0.76 g (19 mmol) of sodium hydride as asuspension in 20 ml of tetrahydrofuran there are added, over a fewminutes, 6.0 g (17.3 mmol) of the compound obtained in the Step above,dissolved in 50 ml of tetrahydrofuran. The mixture is heated at 50° C.for 2 hours and there are then added, all at once, 5.7 g (17.3 mmol) of3,5-dibromobenzyl bromide, and then 6.4 g (17.3 mmol) oftetra-n-butylammonium iodide, and heating is carried out overnight at70° C. The mixture is then poured into 200 ml of water and extractedwith ethyl ether. The combined organic phases are washed and dried.After evaporation and flash chromatography on 500 g of silica (eluant:dichloromethane 100%, then dichloromethane/ethyl acetate 95/5 and thendichloromethane/ethanol 95/5), the expected compound is collected.

Step C:trans-1-{2-[(3,5-Dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}-1,4-diazepanedihydrochloride

Gaseous hydrogen chloride is gently bubbled through 4.9 g (8.2 mmol) ofthe compound obtained in the Step above, dissolved in 250 ml of ethylacetate, at ambient temperature, for a few minutes. Stirring is carriedout overnight at ambient temperature; the mixture is then concentratedby half (a precipitate appears) and stirring is carried out for afurther 2 hours. After filtering off, rinsing and drying theprecipitate, the expected compound is collected in racemic form.

Melting point (M.K.): 112-118° C.

EXAMPLE 19 (−) isomer oftrans-1-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}-1,4-diazepanedihydrochloride

After reconversion to the base, the racemic compound obtained in Example18 is separated by preparative chiral HPLC chromatography on a CHIRALPAKAD column (eluant: methanol/diethylamine 1000/1). The first of theisomers thereby separated is converted into the hydrochloride salt usingethanolic HCl. After filtration, rinsing and drying, the (−) enantiomeris obtained in an enantiomeric excess of more than 98%.

Melting point (M.K.): 122-126° C.

EXAMPLE 20 (+) isomer oftrans-1-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}-1,4-diazepanedihydrochloride

The second of the isomers separated in Example 19 is converted into ahydrochloride to yield the expected product.

Melting point (M.K.): 119-140° C.

EXAMPLE 211-{(1S,2R)-2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-piperazinedihydrochloride Step A:(1S,2R)-1-{4-[(4-Methylphenyl)sulphonyl]piperazin-1-yl}indan-2-ol

To 8 g of (1S,2R)-1-aminoindan-2-ol (53.6 mmol) dissolved in 80 ml ofdimethylformamide there are added 15 ml of triethylamine (107.2 mmol)and 15.8 g of N,N-bis(2-chloroethyl)-p-toluenesulphonamide (53.6 mmol).The mixture is heated at 80° C. for 24 hours and then thedimethylformamide is evaporated off. The residue is taken up indichloromethane, washed, dried, filtered and evaporated. The oilobtained is purified by flash chromatography on silica (eluant:dichloromethane/ethyl acetate 95/5) to yield the expected product in theform of a meringue.

Step B:1-{(1S,2R)-2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-4-[(4-methylphenyl)sulphonyl]piperazine

The expected product is obtained according to the procedure described inStep B of Example 1, starting from the compound obtained in the Stepabove.

Step C:1-{(1S,2R)-2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine

1.1 g of the compound obtained in the Step above (1.77 mmol) are heatedfor 2 hours at 90° C. in the presence of 10 ml of a solution ofHBr/acetic acid (33%) and 808 mg of 4-hydroxybenzoic acid (5.85 mmol).Cooling is carried out and NaOH (20%) is added until the pH=10;extraction with dichloromethane, drying, filtration and evaporation arethen carried out. The oil obtained is purified by flash chromatographyon 100 g of silica (eluant: dichloromethane/ethanol/ammonia 90/10/1) toyield the expected product in the form of a colourless oil.

Step D:1-{(1S,2R)-2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride

To 1.2 g of the compound obtained in the Step above (2.57 mmol),dissolved in ethyl acetate, there are added, at ambient temperature, a2M solution of hydrochloric acid in ether. The mixture is stirred for 30minutes and then evaporated to dryness. The residue is crystallised fromethyl acetate, filtered and dried to yield the expected product (ciscompound) in the form of white crystals.

Melting point (MK): 162-176° C. Optical rotation [α]=−2.9 (c=1%, MeOH,20° C., λ=589 nm)

EXAMPLE 221-{(1R,2S)-2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure described inExample 21, starting from (1R,2S)-1-aminoindan-2-ol.

Melting point (MK): 142-150° C. Optical rotation: [α]=+5.8 (c=1%, MeOH,20° C., λ=589 nm)

EXAMPLE 23cis-1-{4-[(3,5-Dibromobenzyl)oxy]-2,3,4,5-tetrahydro-1-benzoxepin-5-yl}piperazinedihydrochloride Step A: tert-Butyl4-(4-oxo-2,3,4,5-tetrahydro-1-benzoxepin-5-yl)piperazine-1-carboxylate

At −78° C., 0.88 ml of oxalyl chloride (10 mmol) is poured into 25 ml ofdichloromethane and then, at the same temperature, there are slowlyadded 1.02 ml of dimethyl sulphoxide (14.3 mmol). Stirring is carriedout for 10 minutes at −78° C. 2.5 g (7.17 mmol) of the compound obtainedin Step B of Example 8, dissolved in 15 ml of dichloromethane, arepoured into the reaction mixture. Stirring is carried out for 15 minutesat −78° C. and there are then added, over 20 minutes, 5 ml (35.9 mmol)of triethylamine. The mixture is then allowed to return to 0° C. and thereaction mixture is then poured into 100 ml of ice-cold water.Extraction with dichloromethane, drying, filtration and evaporation todryness are carried out to yield the expected product in the form of anoil.

Step B: tert-Butylcis-4-(4-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-5-yl)piperazine-1-carboxylate

To 2.4 g (6.93 mmol) of the compound obtained in the Step above,dissolved in 50 ml of methanol there are added, at 0° C. and inportions,130 mg of NaBH₄ (3.5 mmol, 0.5 of an equivalent). Stirring iscarried out for 1 hour at 0° C. and the methanol is then evaporated off.The residue obtained is taken up in toluene, washed, dried, filtered andevaporated. The residue obtained is purified by flash chromatography onsilica (eluant: toluene/ethanol 95/5) to yield the expected product inthe form of an oil.

Step C:cis-1-{4-[(3,5-Dibromobenzyl)oxy]-2,3,4,5-tetrahydro-1-benzoxepin-5-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure described inSteps B and C of Example 1 starting from the compound obtained in theStep above.

Melting point (MK): 166-191° C.

EXAMPLE 24cis-1-[2-((3,5-Dibromobenzyloxy)-1,2,3,4-tetrahydronaphth-1-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure described inExample 23, starting from the compound obtained in Step C of Example 15.

Melting point (MK): 155-159° C.

EXAMPLE 25 cis-1-{6[(3,5-Dibromobenzyl)oxy]-6,7,8,9-tetrahydro-5H-benzo-[7]annulen-5-yl}piperazinedihydrochloride Step A: tert-Butyl4-(6-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)piperazine-1-carboxylate

To 4.4 g (12.6 mmol) of the compound obtained in Step A of Example 7,dissolved in 44 ml of dimethyl sulphoxide, there are added, at ambienttemperature, 8.8 g of stabilised 2-iodoxybenzoic acid (SIBX) (56.3 mmol,4.4 equivalents). Stirring is carried out for 2 hours at 25° C., and themixture is then poured into water. The insoluble material obtained isfiltered off. The filtrate is extracted with ethyl acetate, dried,filtered and evaporated to dryness. The residue obtained is purified byflash chromatography on silica (eluant: dichloromethane/ethyl acetate95/5) to yield the expected product.

Melting point (BK): 85-95° C.

Step B: tert-Butyl4-(6-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)piperazine-1-carboxylate

1.5 g (4.3 mmol) of the compound obtained in the Step above are treatedaccording to the method described in Step B of Example 23. The yellowoil obtained is purified by flash chromatography on silica (eluant:dichloromethane/ethyl acetate 95/5) to yield the expected product in theform of a cis/trans mixture (cis/trans ratio=80/20).

Step C: tert-Butylcis-4-{6-[(3,5-dibromobenzyl)oxy]-6,7,8,9-tetrahydro-5H-benzo-[7]annulen-5-yl}piperazine-1-carboxylate

650 mg of the compound obtained in the Step above (cis/trans=80/20)(1.87 mmol) are treated according to the method described in Step B ofExample 1 to yield an oil which is purified by flash chromatography onsilica (eluant: cyclohexane/ethyl acetate 95/5) to yield the expectedproduct.

Step D:cis-1-{6-[(3,5-Dibromobenzyl)oxy]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}piperazinedihydrochloride

350 mg of the compound obtained in the Step above (0.58 mmol) aretreated according to the method described in Step C of Example 1, andthen the product obtained is crystallised from isopropyl ether to yieldthe expected product in the form of white crystals.

Melting point (MK): 149-158° C.

EXAMPLE 26trans-3-[(3,5-Dibromobenzyl)oxy]-4-piperazin-1-ylchroman-6-carbonitriledihydrochloride Step A: 6-Bromo-1a,7b-dihydro-2H-oxireno[c]chromene

8.5 g of 6-bromo-2H-chromene (40.3 mmol) prepared according to thesynthesis method described in J. Org. Chem., 1998, 63, 864 are treatedaccording to the method described in Step A of Example 8 to yield theexpected product in the form of an oil.

Step B: tert-Butyltrans-4-(6-bromo-3-hydroxy-3,4-dihydro-2H-chromen-4-yl)piperazine-1-carboxylate

7.6 g of the compound obtained in the Step above (33.5 mmol) are treatedaccording to the method described in Step A of Example 1. The residueobtained is purified by flash chromatography on silica (eluant:toluene/ethanol 95/5) to yield the expected product in the form of anoil.

Step C: tert-Butyltrans-4-(6-cyano-3-hydroxy-3,4-dihydro-2H-chromen-4-yl)piperazine-1-carboxylate

1 g of the compound obtained in the Step above (2.4 mmol) is dissolvedin 10 ml of dimethylformamide. The solution is degassed using argon andthere are then added 112 mg of tetrakis(triphenylphosphine)palladium(0)(0.09 mmol) and 170 mg of zinc cyanide (1.4 mmol). Heating is carriedout at 80° C. for 3 days. The reaction mixture is then cooled and pouredinto water. The mixture is extracted with ethyl acetate, washed withwater, dried, filtered and evaporated to dryness. The residue obtainedis purified by flash chromatography on silica (eluant:dichloromethane/ethyl acetate 90/10) to yield the expected product inthe form of an oil.

Step D:trans-3-[(3,5-Dibromobenzyl)oxy]-4-piperazin-1-ylchroman-6-carbonitriledihydrochloride

The expected product is obtained according to the procedure described inSteps B and C of Example 1, starting from the compound obtained in theStep above.

Melting point (MK): 185-200° C.

EXAMPLE 27trans-7-[(3,5-Dibromobenzyl)oxy]-8-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitriledihydrochloride Step A:6-Bromo-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene

7.4 g of the compound of Preparation A (35 mmol) are treated with Oxone®according to the method described in Step A of Example 8 to yield theexpected product in the form of an oil.

Step B: tert-Butyltrans-4-(7-bromo-2-hydroxy-1,2,3,4-tetrahydronaphth-1-yl)-piperazine-1-carboxylate

6.5 g of tert-butyl piperazine-1-carboxylate (35 mmol) and 7.9 g of thecompound obtained in the Step above (35 mmol) are dissolved in 45 ml ofdimethylformamide, and the reaction mixture is then heated at 110° C.for 24 hours. After evaporation to dryness, there is obtained a residuewhich is purified by flash chromatography on silica (eluant:toluene/ethanol 98/2) to yield the expected product in the form of anoil.

Step C: tert-Butyltrans-4-(7-cyano-2-hydroxy-1,2,3,4-tetrahydronaphth-1-yl)-piperazine-1-carboxylate

4 g of the compound obtained in the Step above (9.7 mmol) are treatedaccording to the method described in Step C of Example 26. Heating iscarried out at 80° C. for 2 hours. The reaction mixture is then cooledand poured into water. The mixture is extracted with dichloromethane,washed with water, dried, filtered and evaporated to dryness. Theresidue obtained is purified by flash chromatography on silica (eluant:dichloromethane/ethanol 98/2) to yield the expected product in the formof an oil.

Step D:trans-7-[(3,5-Dibromobenzyl)oxy]-8-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitriledihydrochloride

The expected product is obtained according to the procedure described inSteps B and C of Example 1, starting from the compound obtained in theStep above.

Melting point (MK): 169-191° C.

EXAMPLE 28trans-4-[(3,5-Dibromobenzyl)oxy]-5-piperazin-1-yl-2,3,4,5-tetrahydro-1-benzoxepin-7-carbonitriledihydrochloride Step A:7-Bromo-1a,2,3,8b-tetrahydrooxireno[d][1]benzoxepin

4 g of the compound of Preparation B are treated with Oxone® accordingto the method described in Step A of Example 8 to yield the expectedproduct in the form of an oil.

Step B: tert-Butyltrans-4-(7-bromo-4-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-5-yl)-piperazine-1-carboxylate

3.9 g of the compound obtained in the Step above (16.2 mmol) are treatedaccording to the method described in Step A of Example 1. Heating iscontinued for a further 3 days. There is thereby obtained a residuewhich is purified by flash chromatography on silica (eluant:dichloromethane/ethanol 98/2) to yield the expected product in the formof an oil.

Step C: tert-Butyltrans-4-(7-cyano-4-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-5-yl)-piperazine-1-carboxylate

5.8 g of the compound obtained in the Step above (13.6 mmol) are treatedaccording to the method described in Step C of Example 26. Heating iscarried out at 80° C. for 20 hours. The reaction mixture is then cooledand poured into water. The mixture is extracted with dichloromethane,washed with water, dried, filtered and evaporated to dryness. Theresidue obtained is purified by flash chromatography on silica (eluant:toluene/ethanol 95/5) to yield the expected product in the form of anoil.

Step D:trans-4-[(3,5-Dibromobenzyl)oxy]-5-piperazin-1-yl-2,3,4,5-tetrahydro-1-benzoxepin-7-carbonitriledihydrochloride

The expected product is obtained according to the procedure described inSteps B and C of Example 1, starting from the compound obtained in theStep above.

Melting point (MK): 163-195° C.

EXAMPLE 29trans-5-[(4-{2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-onedihydrochloride Step A:trans-5-[(4-{2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

After reconversion to the base, the compound obtained in Step C ofExample 1 (2.14 mmol) is dissolved in 30 ml of dimethylformamide. Thereare added 0.75 ml (4.28 mmol) of diisopropylethylamine and 314 mg (2.35mmol) of 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one preparedaccording to the method described in Tetrahedron Letters,2000, 41, 8661.The mixture is stirred for 12 hours at ambient temperature and thenevaporated to dryness. The residue obtained is taken up indichloromethane, washed, dried, filtered and evaporated. The oilobtained is purified by flash chromatography on silica to yield theexpected product.

Step B:trans-5-[(4-{2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazin-1-yl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-onedihydrochloride

800 mg of the compound obtained in the Step above (1.42 mmol) aredissolved in 50 ml of ethyl acetate. 2.8 ml (5.68 mmol) of a 2M solutionof hydrochloric acid in ether are then added. After stirring for 30minutes at ambient temperature, the mixture is evaporated to dryness andthe residue is crystallised from acetonitrile to yield the expectedproduct.

Melting point (MK): 198-202° C.

EXAMPLE 30trans-1-{2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl]piperazinedihydrochloride Step A: tert-Butyl4-[(2R)-2,3-dihydro-1,4-benzodioxin-2-ylcarbonyl]piperazine-1-carboxylate

5 g of (2R)-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid (27.8 mmol)are dissolved in 300 ml of acetonitrile. 6 g ofN,N′-dicyclohexylcarbodiimide (29.1 mmol) and then 4.1 g of1-hydroxybenzotriazole (30.6 mmol) are added. Finally, 6.2 g oftert-butyl piperazine-1-carboxylate (33.4 mmol) are added and stirringis carried out for 12 hours at ambient temperature. The reaction mixtureis subsequently filtered and the filtrate is then evaporated to dryness.The oil thereby obtained is purified by flash chromatography on silica(eluant: toluene/ethyl acetate 80/20) to yield the expected product inthe form of an oil.

Step B: tert-Butyl4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl]piperazine-1-carboxylate

500 mg of the compound obtained in the Step above (1.44 mmol) aredissolved in 5 ml of anhydrous tetrahydrofuran. There are then addeddropwise, at ambient temperature, 4.4 ml (4.3 mmol) of a 1M solution ofborane in tetrahydrofuran. The mixture is heated at reflux for 2 hours,cooled, hydrolysed slowly using 5 ml of ethanol, and evaporated todryness. The residue obtained is crystallised from water, filtered anddried to yield the expected product.

Melting point (BK)=97-99° C.

Step C: 1-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-ylmethyl]piperazinedihydrochloride

7.5 g of the compound obtained in the Step above (22.4 mmol) are stirredfor 2 days, at ambient temperature, in the presence of 100 ml of a 2.6Nsolution of hydrochloric acid in ethanol. The crystals formed arefiltered off and dried to yield the expected product in the form of awhite solid.

Melting point (BK)=166-172° C.

Step D: trans1-{4-[(2S)-2,3-Dihydro-1,4-benzodioxin-2-ylmethyl]piperazin-1-yl}indan-2-ol

To 1.6 g (6.8 mmol) of1-[(2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl]piperazine, obtained byreconverting the compound of the above Step to the base, dissolved in 10ml of acetonitrile, there are added 1.08 g of indene oxide (8.16 mmol).The reaction mixture is heated at 80° C. for 30 hours and thenevaporated to dryness. The oil thereby obtained is purified by flashchromatography on silica (eluant: dichloromethane/ethanol/ammonia90/10/1) to yield the expected compound in the form of a meringue.

Step E:trans-1-{2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl]piperazine

The expected product is obtained according to the procedure described inStep B of Example 1, starting from the compound obtained in the Stepabove.

Step F:trans-1-{2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-4-[(2S)-2,3-dihydro-1,4-benzodioxin-2-ylmethyl]piperazinedihydrochloride

To 210 mg of the compound obtained in the Step above (0.34 mmol),dissolved in 20 ml of ethyl acetate, there are added, at ambienttemperature, 0.5 ml (1 mmol) of a 2M solution of hydrochloric acid inether. After stirring for 30 minutes, the reaction mixture is evaporatedto dryness. The residue obtained is crystallised from ethyl acetate,filtered and dried to yield the expected product in the form of whitecrystals.

Melting point (MK): 137-145° C.

EXAMPLE 31(+)-cis-1-{(1S,2R)-2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-4-(pyridin-2-ylcarbonyl)piperazinedihydrochloride Step A:cis-1-{(1S,2R)-2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-4-(pyridin-2-ylcarbonyl)piperazine

To 263 mg of pyridine-2-carboxylic acid (2.14 mmol), dissolved in 10 mlof tetrahydrofuran, there are added 382 mg of carbonyldiimidazole (2.35mmol, 1.1 equivalents) and then, after stirring for 3 hours at ambienttemperature, a solution of 1 g (2.14 mmol) of the compound obtained inStep C of Example 21 in 20 ml of tetrahydrofuran. Stirring for 12 hoursat 25° C., and then addition of water, extraction with dichloromethane,drying, filtration and evaporation to dryness are carried out. The oilobtained is purified by flash chromatography on silica (eluant:dichloromethane/ethanol 95/5) to yield the expected product in the formof an oil.

Step B:cis-1-{(1S,2R)-2-[(3,5-Dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-4-(pyridin-2-ylcarbonyl)piperazinedihydrochloride

900 mg of the compound obtained in the Step above (1.57 mmol) aretreated according to the method described in Step F of Example 30. Thesolid obtained is filtered off and dried to yield the expected productin the form of white crystals.

Melting point (MK): 108-122° C. Optical rotation [α]=+27.3 (c=1%,methanol, 20° C., λ=589 nm)

EXAMPLE 321-(trans-2-{1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-1,2,3,4-tetrahydronaphth-1-yl)piperazinedihydrochloride, diastereoisomer 1 Step A: tert-Butyl4-(trans-2-{[3,5-bis(trifluoromethyl)benzoyl]oxy}-1,2,3,4-tetrahydronaphth-1-yl)piperazine-1-carboxylate

To 11.7 g (35.2 mmol) of the compound obtained in Step C of Example 15and 5.9 ml (42.2 mmol) of triethylamine, dissolved in 300 ml ofdichloromethane, there are added, at ambient temperature, 7.05 ml (38.7mmol) of bis(trifluoromethyl)benzoyl chloride in 50 ml ofdichloromethane, dropwise over 1 hour 10 minutes, and then 0.5 g ofdimethylaminopyridine. The reaction mixture is then heated at reflux for5 days, and then a further 1.3 ml of the acid chloride are added andrefluxing is continued for 20 hours. After evaporation of the medium,the residue obtained is filtered over 200 g of silica (eluant:dichloromethane) to yield the expected product.

Step B: tert-Butyl4-[trans-2-({1-[3,5-bis(trifluoromethyl)phenyl]vinyl}oxy)-1,2,3,4-tetrahydronaphth-1-yl]piperazine-1-carboxylate

To 13.2 g (23 mmol) of the compound obtained in the Step above in 92 mlof tetrahydrofuran there are added, at ambient temperature, 46 ml of a1M solution of dicyclopentadienyldimethyltitanium in toluene, and thereaction mixture is heated at 85° C. for 20 hours. A further 23 ml ofthe 1M solution of dicyclopentadienyldimethyltitanium in toluene areadded, dropwise, at 85° C. over 10 minutes, and then heating at thattemperature is continued for a further 24 hours. The mixture is allowedto cool, 500 ml of pentane are added; the mixture is filtered overCelite and rinsed with pentane until the filtrate is colourless. Afterevaporation of all the combined filtrates and flash chromatography on800 g of silica (eluant: dichloromethane, and then dichloromethane/ethylacetate 98/2), the expected product is obtained.

Step C: tert-Butyl4-(trans-2-{1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1,2,3,4-tetrahydronaphth-1-yl)piperazine-1-carboxylate

8.34 g (14.6 mmol) of the compound obtained in the Step above, dissolvedin 150 ml of ethanol, are hydrogenated at ambient temperature andatmospheric pressure for 7 hours in the presence of 1 g of 5%palladium-on-carbon. After filtration over Celite, rinsing with ethanoland evaporation, the expected product is obtained in the form of anon-quantifiable and non-separable mixture of diastereoisomers.

Step D:1-(trans-2-{1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-1,2,3,4-tetrahydronaphth-1-yl)piperazinedihydrochloride, diastereoisomer 1

Gaseous hydrogen chloride is gently bubbled through 8.4 g (14.6 mmol) ofthe compound obtained in the Step above, dissolved in 500 ml of ethylacetate, at ambient temperature for a few minutes. Stirring overnight atambient temperature and then evaporation to dryness are carried out. Theresidue is dissolved in 100 ml of water and, with vigorous stirring, isconverted to the base using 8 g of sodium carbonate. The paste whichprecipitates out is extracted twice using 100 ml of dichloromethane eachtime. The combined organic phases are dried and concentrated, and theresidue obtained is chromatographed on 700 g of silica (eluant:dichloromethane/ethanol/ammonia 95/5/0.5) to yield the firstdiastereoisomer, which is converted to the dihydrochloride by the actionof ethereal HCl. After crystallisation from pentane, the expectedproduct is obtained.

Melting point (M.K.): 98-102° C.

EXAMPLE 331-(trans-2-{1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}-1,2,3,4-tetrahydronaphth-1-yl)piperazinedihydrochloride, diastereoisomer 2

The second product eluted in Step D of Example 32 yields the seconddiastereoisomer, which is converted to the dihydrochloride.

Melting point (M.K.): 98-101° C.

EXAMPLE 34 1-[(1S,2R)-2-Benzyloxy-2,3-dihydro-1H-inden-1-yl]piperazinedihydrochloride

The expected product (cis compound) is obtained according to theprocedure of Example 21, replacing the 3,5-dibromobenzyl bromide in StepB by benzyl bromide.

Melting point: 104-125° C.

EXAMPLE 35trans-1-{2-[(3,5-Dimethylbenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure described inSteps D and E of Example 15, starting from the compound obtained in StepA of Example 1 and 3,5-dimethylbenzyl bromide.

Melting point: 161-70° C.

EXAMPLE 361-[(1S,2R)-2-[(3,5-Difluorobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl]-piperazinedihydrochloride

The expected product (cis compound) is obtained according to theprocedure of Example 21, replacing the 3,5-dibromobenzyl bromide in StepB by 3,5-difluorobenzyl bromide.

Melting point: 160-190° C.

EXAMPLE 371-[(1S,2R)-2-Benzyloxy-2,3-dihydro-1H-inden-1-yl]4-methylpiperazinedihydrochloride

The expected product is obtained by N-methylation of the compound ofExample 34.

Melting point: 182-189° C.

EXAMPLE 381-[(1S,2R)-2-[(3,5-Dimethylbenzyl)oxy]-2,3-dihydro-1H-inden-1-yl]-piperazinedihydrochloride Step A:1-{(1S,2R)-2-[(3,5-Dimethylbenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-4-[(4-methylphenyl)sulphonyl]piperazine

The expected product is obtained according to the procedure described inSteps A and B of Example 21, replacing the 3,5-dibromobenzyl bromide inStep B by 3,5-dimethylbenzyl bromide.

Step B:1-{(1S,2R)-2-[(3,5-Dimethylbenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine

3 g of sodium (130 mmol) are added to a solution of 3.6 g of naphthalene(28 mmol) in 30 ml of 1,2-dimethoxyethane. The reaction mixture isstirred at ambient temperature for 2 hours to form thesodium/naphthalene/1,2-dimethoxyethane solution. 14.8 ml (64 mmol) ofthe resulting solution are added, at a temperature of −70° C., to asolution of 3 g (6.1 mmol) of the compound obtained in the Step above in55 ml of 1,2-dimethoxyethane. The colour of the solution changes fromwhite to blue. Stirring is carried out for 30 minutes at −70° C.,followed by hydrolysis using 100 ml of water. The mixture is thenextracted with ethyl acetate, dried, filtered and evaporated to dryness.The residue obtained is purified by flash chromatography on 200 g ofsilica (eluant: dichloromethane/ethanol/ammonia 90/10/1) to yield theexpected product in the form of an oil.

Step C:1-{(1S,2R)-2-[(3,5-Dimethylbenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride

3.6 ml (7.16 mmol, 2 equivalents) of a 2M solution of ethereal hydrogenchloride are added to 1.2 g (3.58 mmol) of the compound obtained in theStep above in 50 ml of acetonitrile. Crystallisation is initiated byscratching, and then stirring is carried out for 15 minutes at ambienttemperature. The white crystals obtained are dried to yield the expectedproduct.

Melting point: 170-193° C.

EXAMPLE 39trans-1-{2-[(3,5-Difluorobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure of Example1, replacing the 3,5-dibromobenzyl bromide in Step B by3,5-difluorobenzyl bromide.

Melting point: 185-198° C.

EXAMPLE 40trans-1-(2-{[3,5-Bis(trifluoromethyl)benzyl]oxy}-2,3-dihydro-1H-inden-1-yl)piperazinedihydrochloride

The expected product is obtained according to the procedure of Example1, replacing the 3,5-dibromobenzyl bromide in Step B by3,5-bis(trifluoromethyl)benzyl bromide.

Melting point: 140-160° C.

EXAMPLE 41trans-1-{2-[(3,5-Dibromobenzyl)oxy]-6-methoxy-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 2H-chromene in Step A by 5-methoxy-1H-indene.

Melting point: 184-195° C.

EXAMPLE 42trans-1-{2-[(3,5-Dichlorobenzyl)oxy]-6-methoxy-2,3-dihydro-1H-inden-1-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, starting from 5-methoxy-1H-indene and 3,5-dichlorobenzyl bromide.

Melting point: 169-176° C.

EXAMPLE 43trans-1-{2-[(3,5-Dichlorobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure of Example1, replacing the 3,5-dibromobenzyl bromide in Step B by3,5-dichlorobenzyl bromide.

Melting point: 115-127° C.

EXAMPLE 44trans-1-{3-[(3,5-Dichlorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by3,5-dichlorobenzyl bromide.

Melting point: 110-118° C.

EXAMPLE 45trans-1-{2-[(3,5-Bis(trifluoromethyl)benzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example15, replacing the 3,5-dibromobenzyl bromide in Step D by3,5-bis(trifluoromethyl)benzyl bromide.

Melting point (MK): 98-101° C.

EXAMPLE 46trans-1-{3-[3-Fluoro-5-(trifluoromethyl)benzyloxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by3-fluoro-5-(trifluoromethyl)benzyl bromide.

Melting point: 102-113° C.

EXAMPLE 47trans-1-{3-(3-Chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride Step A: tert-Butyltrans-4-{3-[(3-chloro-5-fluorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazine-1-carboxylate

The expected product is obtained according to the procedure described inSteps A to D of Example 4, replacing the 3,5-dibromobenzyl bromide inStep D by 3-chloro-5-fluorobenzyl bromide.

Step B:trans-1-{3-(3-Chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure described inStep C of Example 1, starting from the compound obtained in the Stepabove.

Melting point: 90-95° C.

EXAMPLE 47 bistrans-1-{3-(3-Chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazinedimethanesulphonate

The expected product is obtained by reaction of the compound of Example47 with sodium hydroxide, followed by conversion of the product therebyobtained into a salt using methanesulphonic acid.

Melting point: 161-171° C.

EXAMPLE 48cis-4-[2-(3,5-Dibromobenzyloxy)-1,2,3,4-tetrahydronaphth-1-yl]-morpholinehydrochloride

The expected product is obtained according to the procedure of Example23, replacing, in Step A, the compound obtained in Step B of Example 8by the compound obtained in Step B of Example 10.

Melting point: 195-198° C.

EXAMPLE 49trans-4-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}morpholinehydrochloride

The expected product is obtained according to the procedure described inSteps B to D of Example 10, starting from the compound obtained in StepB of Example 4.

Melting point: 143-148° C.

EXAMPLE 50trans-4-{2-[(3,5-Dibromobenzyl)oxy]-1,2,3,4-tetrahydro-1-naphthyl}-piperidinehydrochloride Step A: 1-(4-Pyridyl)-1,2,3,4-tetrahydro-1-naphthol

85 ml of a 1.5M solution of n-butyllithium in hexane are added,dropwise, to a solution of 20 g of 4-bromopyridine in 73 ml of ether,cooled to −78° C. Stirring is carried out for 30 minutes at thattemperature, a solution of 1-tetralone in 73 ml of ether is then pouredin and, at the end of the addition, the mixture is allowed to return toambient temperature. After stirring overnight, a saturated aqueoussolution of ammonium chloride is poured in. After separation, extractionwith ether is carried out. The ethereal phases are combined andextracted with 1N hydrochloric acid. The combined acid phases areadjusted to pH=8 using 20% sodium hydroxide solution and extracted withdichloromethane. After drying, the expected product is isolated, whichis purified by high-speed chromatography on silica (eluant:dichloromethane/methanol 95/5) to yield the expected product.

Melting point (B.K.)=160-162° C.

Step B: 4-(3,4-Dihydro-1-naphthyl)pyridine

2 g of the compound obtained in the Step above, 10 ml of water and 10 mlof sulphuric acid 95% are mixed together, heated at 80° C. for 30minutes, cooled to 0° C. and adjusted to pH=10 using 20% sodiumhydroxide solution. The mixture is extracted with dichloromethane,washed with water, dried and evaporated to yield the expected product.

Step C: 4-(2,3-Dihydronaphtho[1,2-b]oxiren-7b(1aH)-yl)pyridine 1-oxide

At a temperature of from 20 to 25° C., a solution containing 5.4 g ofthe product obtained in the Step above, 20 g of sodium bicarbonate, 35ml of acetone, 20 ml of water and 200 ml of ethyl acetate is poured intoa solution of 29.3 g of Oxone® in 200 ml of water. Stirring overnight atambient temperature, dilution with water and extraction with ethylacetate are carried out. After conventional treatment, the expectedproduct is isolated.

Step D: 1-(1-Oxido-4-pyridyl)-1,2,3,4-tetrahydro-2-naphthol

To a solution of 450 mg of the product obtained in the Step above in 10ml of anhydrous tetrahydrofuran, in the presence of a trace ofBromocresol Green, there are added, all at once and at ambienttemperature, 289 mg of sodium cyanoborohydride. Boron trifluorideetherate is added until the coloured indicator turns yellow and as manytimes as necessary in the course of the reaction to maintain the pH at4-5. At the end of the reaction, concentrated hydrochloric acid is addeduntil the pH=1, and stirring is carried out for 30 minutes at ambienttemperature. The mixture is adjusted to pH=8 using sodium hydroxidesolution and extracted with ethyl acetate, and after treatment theexpected product is isolated (80% trans, 20% cis).

Step E: 1-(4-Piperidyl)-1,2,3,4-tetrahydro-2-naphthol

1.78 g of the product obtained in the Step above, 1 g of platinum oxide,0.75 ml of concentrated hydrochloric acid and 75 ml of ethanol are mixedin a reactor and hydrogenated under a pressure of 1 bar. After reactingfor 6 hours at ambient temperature, filtration is carried out; 8 ml ofsodium hydroxide solution are added, the ethanol is evaporated off, aminimum amount of water is used for dissolution and the pH is adjustedto 10. After extraction and conventional treatment, the expected productis obtained (80% trans, 20% cis).

Step F: tert-Butyl4-(2-hydroxy-1,2,3,4-tetrahydro-1-naphthyl)-1-piperidinecarboxylate

A solution of 2.1 g of di(tert-butyl) dicarbonate in 50 ml ofdichloromethane is added to 2.06 g of the product obtained in the Stepabove, dissolved in 50 ml of dichloromethane. Stirring is carried outfor two hours at ambient temperature, followed by evaporation todryness. After purification on silica (eluant: dichloromethane/methanol95/5), the expected product is isolated (80% trans, 20% cis).

Step G: tert-Butyl4-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydro-1-naphthyl}-1-piperidinecarboxylate

241 mg of sodium hydride 60% in oil are introduced into a solution of1.9 g of the compound obtained in the Step above in 20 ml of anhydroustetrahydrofuran, cooled to 0° C. Stirring is carried out for 15 minutesand there are then added, still at that temperature, 20 mg oftetrabutylammonium iodide and finally 1.9 g of 3,5-dibromobenzylbromide. The mixture is allowed to return to ambient temperature and isstirred for 24 hours. The mixture is evaporated to dryness, taken up inwater and dichloromethane and, after conventional treatment andchromatography on silica (eluant: dichloromethane), the expected productis isolated in the form of a white meringue (80% trans, 20% cis).

Step H:trans-4-{2-[(3,5-Dibromobenzyl)oxy]-1,2,3,4-tetrahydro-1-naphthyl}piperidinehydrochloride

2 g of the compound obtained in the Step above, in 20 ml of ethanol, aretreated with 19 ml of a 3.6N solution of ethanolic hydrogen chloride.After 24 hours, the precipitate formed is filtered off, rinsed and driedto yield the expected product in the form of the hydrochloride. (The ciscompound is in the filtrate).

Melting point: 152-167° C.

EXAMPLE 51cis-1-Acetyl-3-[(3,5-dibromobenzyl)oxy]-4-(1-piperazinyl)-1,2,3,4-tetrahydroquinolinedihydrochloride Step A: 1-Acetyl-1,2-dihydroquinoline

23.43 g of sodium borohydride are introduced, in portions, into asolution of 20 g of quinoline in 200 ml of acetic acid and 77.5 ml ofacetic anhydride, cooled to 0° C. The mixture is then heated for 2 hoursat 60° C. and is stirred overnight at ambient temperature. The mixtureis concentrated, diluted with water, adjusted to pH=10 with sodiumhydroxide solution and extracted with ether. The combined etherealphases are washed with 1N hydrochloric acid and then at neutral pH andafter conventional treatment the expected product is isolated.

Step B: 3-Acetyl-1a,2,3,7b-tetrahydrooxireno[2,3-c]quinoline

The expected product is obtained according to the procedure described inStep A of Example 8, starting from the compound obtained in the Stepabove.

Step C: tert-Butyltrans-4-[1-acetyl-3-hydroxy-1,2,3,4-tetrahydro-4-quinolyl]-1-piperazinecarboxylate

The expected product is obtained according to the procedure described inStep A of Example 1, starting from the compound obtained in the Stepabove.

Step D:cis-1-Acetyl-3-[(3,5-dibromobenzyl)oxy]-4-(1-piperazinyl)-1,2,3,4-tetrahydroquinolinedihydrochloride

The expected product is obtained according to the procedure of Example23, starting from the compound obtained in the Step above.

Melting point: 164-167° C.

EXAMPLE 52trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-N-methyl-4-piperidinaminedihydrochloride Step A: tert-Butyltrans-1-{3-[(3,5-dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-N-methyl-4-piperidylcarbamate

0.2 g of sodium hydride (60% in oil) is added to 1 g of the compoundobtained in Step B of Example 9 and 0.42 ml of methyl iodide in 10 ml oftetrahydrofuran, maintaining the temperature of the reaction mixture at0° C. After 15 minutes at that temperature, the mixture is stirred for48 hours at ambient temperature, diluted with water and extracted withethyl acetate. After conventional treatment, the expected product isisolated.

Step B:trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-N-methyl-4-piperidinaminedihydrochloride

The expected product is obtained according to the procedure described inStep C of Example 1, starting from the compound obtained in the Stepabove.

Melting point: 192-195° C.

EXAMPLE 53trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-N,N-dimethyl-4-piperidinaminedihydrochloride Step A:trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-N-methyl-4-piperidinamine

The expected product is obtained by reconverting the compound of Example52 to the base.

Step B:trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-N,N-dimethyl-4-piperidinamine

The expected product is obtained according to the procedure described inStep A of Example 52, starting from the compound obtained in the Stepabove.

Step C:trans-1-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-N,N-dimethyl-4-piperidinaminedihydrochloride

The expected product is obtained by conversion of the compound obtainedin the Step above into a salt using hydrochloric acid.

Melting point: 187-190° C.

EXAMPLE 54trans-1-{3-[(3,5-Dimethoxybenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by3,5-dimethoxybenzyl bromide.

Melting point: 108-115° C.

EXAMPLE 55 trans-1-{3-Benzyloxy-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by benzyl bromide.

Melting point: 66-80° C.

EXAMPLE 56trans-1-{3-[(3-Fluorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by 3-fluorobenzylbromide.

Melting point: 180-184° C.

EXAMPLE 57trans-1-{3-[(3-Chlorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by 3-chlorobenzylbromide.

Melting point: 97-107° C.

EXAMPLE 58trans-1-{3-[(3,4-Dichlorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by3,4-dichlorobenzyl bromide.

Melting point: 114-121° C.

EXAMPLE 59trans-1-{2-[(3-Chloro-5-fluorobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazinedimethanesulphonate Step A:trans-1-{2-[(3-Chloro-5-fluorobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure described inSteps B and C of Example 1, replacing the 3,5-dibromobenzyl bromide inStep B by 3-chloro-5-fluorobenzyl bromide.

Step B:trans-1-{2-[(3-Chloro-5-fluorobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}-piperazinedimethanesulphonate

The expected product is obtained by reconverting the compound obtainedin the Step above to the base, followed by conversion into a salt usingmethanesulphonic acid.

Melting point: 175-182° C.

EXAMPLE 60trans-1-{3-[(3-(Trifluoromethyl)benzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedimethanesulphonate Step A:trans-1-{3-[(3-(Trifluoromethyl)benzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by3-(trifluoromethyl)benzyl bromide.

Step B:trans-1-{3-[(3-(Trifluoromethyl)benzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-piperazinedimethanesulphonate

The expected product is obtained by reconverting the compound obtainedin the Step above to the base, followed by conversion into a salt usingmethanesulphonic acid.

Melting point: 123-127° C.

EXAMPLE 61trans-1-{3-[(3-Cyanobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-piperazinedimethanesulphonate Step A:trans-1-{3-[(3-Cyanobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by 3-cyanobenzylbromide.

Step B:trans-1-{3-[(3-Cyanobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedimethanesulphonate

The expected product is obtained by reconverting the compound obtainedin the Step above to the base, followed by conversion into a salt usingmethanesulphonic acid.

Melting point: 118-121° C.

EXAMPLE 62 (+) isomer oftrans-1-{3-(3-chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazinedibenzoyltartrate (+) Step A: (+) isomer of tert-butyltrans-4-{3-[(3-chloro-5-fluorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazine-1-carboxylate

The expected compound is obtained by separation, by means of preparativechiral HPLC chromatography, of the racemic mixture obtained in Step A ofExample 47.

Step B: (+) isomer oftrans-1-{3-(3-chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure described inStep C of Example 1, starting from the compound obtained in the Stepabove.

Step C: (+) isomer oftrans-1-{3-(3-chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazinedibenzoyltartrate (+)

The expected product is obtained by reconverting the compound obtainedin the Step above to the base, followed by conversion into a salt using(+)-dibenzoyltartaric acid.

Melting point: 100-107° C.

EXAMPLE 63 (−) isomer oftrans-1-{3-(3-chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazinedibenzoyltartrate (−) Step A: (−) isomer of tert-butyltrans-4-{3-[(3-chloro-5-fluorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazine-1-carboxylate

The expected compound is the second of the enantiomers separated in StepA of Example 62.

Step B: (−) isomer oftrans-1-{3-(3-chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure described inStep C of Example 1, starting from the compound obtained in the Stepabove.

Step C: (−) isomer oftrans-1-{3-(3-chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazinedibenzoyltartrate (−)

The expected product is obtained by reconverting the compound obtainedin the Step above to the base, followed by conversion into a salt using(−)-dibenzoyltartaric acid.

Melting point: 100-107° C.

EXAMPLE 64trans-1-{3-[(3,5-Difluorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedimethanesulphonate Step A:trans-1-{3-[(3,5-Difluorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by3,5-difluorobenzyl bromide.

Step B:trans-1-{3-[(3-Difluorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedimethanesulphonate

The expected product is obtained by reconverting the compound obtainedin the Step above to the base, followed by conversion into a salt usingmethanesulphonic acid.

Melting point: 178-182° C.

EXAMPLE 65trans-4-{3-[(3,5-Dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}-piperidinehydrochloride

The expected product is obtained according to the procedure of Example50, replacing, in Step A, 1-tetralone by 2,3-dihydro-4H-chromen-4-one.

Melting point: 148-167° C.

EXAMPLE 66trans-1-{3-[(3-(Trifluoromethoxy)benzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedimethanesulphonate Step A:trans-1-{3-[(3-(Trifluoromethoxy)benzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedihydrochloride

The expected product is obtained according to the procedure of Example4, replacing the 3,5-dibromobenzyl bromide in Step D by3-(trifluoromethoxy)benzyl bromide.

Step B:trans-1-{3-[(3-(Trifluoromethoxy)benzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazinedimethanesulphonate

The expected product is obtained by reconverting the compound obtainedin the Step above to the base, followed by conversion into a salt usingmethanesulphonic acid.

Melting point: 132-135° C.

Pharmacological Study of Compounds of the Invention EXAMPLE 67Determination of the Affinity for Serotonin Reuptake Sites in the Rat

The affinity of the compounds for the serotonin (5-HTT) reuptake site isevaluated by competition experiments with [³H]-citalopram on rat frontalcortex membranes. The cortices are homogenised using a Polytron in 40volumes (weight/volume) of cold Tris-HCl (50 mM, pH 7.4) incubationbuffer containing 120 mM NaCl and 5 mM KCl and are then centrifuged fora first time. The sediment is resuspended in the same buffer, incubatedfor 10 minutes at 37° C. and then re-centrifuged. The membranes arewashed a further two times and the sediment is then resuspended in anappropriate volume of incubation buffer. The membranes are thenincubated for 2 hours at 25° C. with the compound under test in thepresence of 0.7 nM [³H]-citalopram. Non-specific binding is determinedwith 10 μM fluoxetine. At the end of the incubation period, the samplesare filtered through Unifilter GF/B type filters pretreated with PEI(0.5%) and washed several times with the incubation buffer. Theradioactivity retained on the filters is counted after addition ofscintillation liquid, with the aid of a scintillation counter. Theisotherms obtained are analysed by non-linear regression to determinethe IC₅₀ values, which are converted into K_(i) using the Cheng-Prusoffequation:K _(i) =IC ₅₀/(1+L/k _(D))wherein L represents the concentration of radioligand and k_(D) is thedissociation constant of [³H]-citalopram on the serotonin reuptake site(0.7 nM). The results are expressed as pK_(i)=−log K_(i).

The results obtained for representative compounds of the invention arecollated in the following table:

Compound pK_(i) r5-HTT Example 1 8.35 Example 4 7.10 Example 21 7.91Example 36 8.97 Example 38 8.73 Example 42 7.71 Example 44 7.31 Example47 7.45

EXAMPLE 68 hNK₁ binding

The affinity of compounds of the invention was determined by competitionexperiments in the presence of [³H]-Substance P (Sar-9,MetO2-11,2-propyl-3,4-3H). IM9 human lymphoblast cells endogenouslyexpressing NK₁ receptors are centrifuged and taken up in the incubationbuffer containing 50 mM TRIS, 150 mM NaCl, 4 mM CaCl₂, proteaseinhibitors at 1/100^(e) (Cocktail SIGMA P8340) and 0.2% BSA. The volumeof incubation buffer is determined so as to obtain a concentration of5×10⁶ cells/ml. The cell preparation is then incubated together with 1.5nM [³H]-Substance P and the compound under test for 90 minutes atambient temperature. Non-specific binding is determined in the presenceof 1 μM GR 205171.

At the end of the incubation period, the samples are filtered throughUnifilter GF/B type filters pretreated with PEI (0.1%) and washedseveral times with the filtration buffer (50 mM TRIS, 150 mM NaCl, 4 mMCaCl₂). The radioactivity retained on the filters is measured bycounting after addition of scintillation liquid to the filters. Thecounts are analysed by non-linear regression, allowing the isotherms tobe plotted and the IC₅₀ values to be determined. The latter are thenconverted into inhibition constants (K_(i)) by means of theCheng-Prusoff equation:K _(i) =IC ₅₀/(1+L/K _(D))wherein L is the concentration of [³H]-Substance P and K_(D) is thedissociation constant of [³H]-Substance P for human NK₁ receptors (0.53nM). The results are expressed as pK_(i) (−log K_(i)).

The results obtained for representative compounds of the invention arecollated in the following table:

Compound pK_(i) NK_(l) Example 1 6.84 Example 4 8.25 Example 7 8.14Example 8 7.54 Example 9 7.96 Example 13 6.60 Example 15 7.48 Example 197.40 Example 40 6.85

EXAMPLE 69 pharmaceutical composition

Formula for the preparation of 1000 tablets each containing 10 mg ofactive ingredient:

Compound of Example 1 10 g Hydroxypropylcellulose 2 g Wheat starch 10 gLactose 100 g Magnesium stearate 3 g Talc 3 g

1. A compound selected from those of formula (I):

wherein: R₁, R₁, R₂, R₃ and R₄, which may be the same or different, eachrepresent an atom or group selected from hydrogen, halogen, linear orbranched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, phenyl and cyano, Xrepresents a bond, an oxygen atom or a group selected from —(CH₂)_(m)—,—OCH₂— and —NR₅—, m represents 1 or 2, R₅ represents a hydrogen atom ora group selected from linear or branched C₁-C₆alkyl, COR₆ and CO₂R₆, R₆represents a linear or branched C₁-C₆alkyl group, Y represents NR₇, R₇represents a hydrogen atom or a group selected from COR₉ and linear orbranched C₁-C₆alkyl, the alkyl group being optionally substituted by a5-oxo-4,5-dihydro- 1H-1,2,4-triazol-3-yl or2,3-dihydro-1,4-benzodioxin-2-yl group, R₉ represents a group selectedfrom linear or branched C₁-C₆ alkyl, aryl and pyridyl, Z represents anitrogen atom, n represents 1, Ak represents a linear or branchedC₁-C₆alkylene chain, Ar represents an aryl group, its optical isomers,and addition salts thereof with a pharmaceutically acceptable acid, itbeing understood that an aryl group means phenyl, biphenylyl ornaphthyl, each of the groups optionally being substituted by one or moreidentical or different groups selected from halogen, linear or branchedC₁-C₆alkyl, linear or branched C₁-C₆alkoxy, hydroxy, cyano, linear orbranched C₁-C₆trihaloalkyl and linear or branched C₁-C₆trihaloalkoxy. 2.The compound of claim 1, wherein Y represents NH.
 3. The compound ofclaim 1, wherein Ar represents an aryl group.
 4. The compound of claim1, wherein X represents a bond, an oxygen atom or a group selected from—OCH₂— and —(CH₂)_(m)— wherein m represents 1 or
 2. 5. The compound ofclaim 1 selected from:trans-1-{2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid,trans-1-{3-[(3,5-dibromobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid,trans-1-{6-[(3,5-dibromobenzyl)oxy]-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl}-piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid,trans-1-{2-[(3,5-dibromobenzyl)oxy]-1,2,3,4-tetrahydronaphth-1-yl}piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid,1-{(1S,2R)-2-[(3,5-dibromobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid,1-[(1S,2R)-2-[(3,5-difluorobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl]piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid,1-[(1S,2R)-2-[(3,5-dimethylbenzyl)oxy]-2,3-dihydro-1H-inden-1-yl]piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid,trans-1-{3-[(3,5-dichlorobenzyl)oxy]-3,4-dihydro-2H-chromen-4-yl}piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid,trans-1-{3-[3-fluoro-5-(trifluoromethyl)benzyloxy]-3,4-dihydro-2H-chromen-4-yl}-piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid,trans-1-{3-(3-chloro-5-fluorobenzyloxy)-3,4-dihydro-2H-chromen-4-yl}piperazine,its enantiomers, and addition salts thereof with a pharmaceuticallyacceptable acid, and enatiomers and addition salts thereof with apharmaceutically acceptable acid.
 6. A pharmaceutical compositioncomprising as active ingredient a compound of claim 1, in combinationwith one or more pharmaceutically acceptable, inert, non-toxic carriers.7. A method for treating a living animal body, including a human,afflicted with a condition selected from depressive states, comprisingthe step of administering to the living animal body, including a human,an amount of a compound of claim 1 which is effective for alleviation ofthe condition.